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We are in the process of researching and plan to establish a vancomycin
extended interval protocol within the next six months. I would be
interested in hearing from other hospital pharmacist about established
programs and their recommendations for implimentation. Our Gentamycin
extended interval program has proven to be a great success. Any
information
or sources would be greatly appreciated.
Karen L. Sears
ksears.aaa.innet.com
Dade City, Fl
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An extended interval protocol is inconsistent with the pharmacodynamics of
vancomycin. The drug has time dependent killing; once above the MIC or MBC by
the appropriate concentration depending upon the organism, further increases
in concentration do not enhance bacterial killing only time of exposure.
Extended intervals may expose some patients to concentrations less than MIC or
MBC which may increase the risk for inadequate response or bacterial
resistance. I believe this is an area in which some work can be done for
patients with some impairment of renal function. Patients with normal renal
function and serious gram positive infections may not be good candidates for
extended dosing intervals. I would like to hear others responses to this
issue.
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I would agree that extended interval vancomycin would be clinically
inappropriate. I think if anything a continuous infusion model would be more
appropriate (getting the steady state concentration above the organism's
MIC).
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I would like to reply to two recent comments
1. Karen L. Sears
I agree with the recent comments of David Nix and Michael Burton that
extended interval vancomycin dosing is not in keeping with its PD profile.
There has been a considerable body of information that has demonstrated a
time-dependent kill pattern with glycopeptides (I include teicoplanin in
this argument) and therefore constant concentrations above the MIC/MBC are
most appropriate. We, in our hospital, have gone towards smaller more
regular doses eg 500 mg q6h rather than 1000 mg q12h as our standard for
patients with normal renal function.
However the difficulty of sending patients home with vancomycin is
considerable and for this we tend to use once-daily dosing, or use
teicoplanin (as it doesn't seem to cause red man syndrome). I therefore
think that there may be some circumstances in which extended interval
dosing may be considered necessary and some work in this area would be
useful.
2. David Nix
I read with interest your detailed response to Karen. I have one question
and a couple of comments:
You say [refering to aminoglycosides] ...
> The AUC relative to the MIC is also
> correlated with efficacy.
I agree with the principle, have you any references, particularly in the
clinical setting? This is an important point since we dose individualise
patients based on acheiving the highest Cmax within a tolerable range of
AUCs.
Comments:
(1) you say ...
> Despite the success, I remain concerned about 2 groups of patients
> that are treated with pulse dosing (once a day aminoglycoside). The
> first group is young patients that eliminate the aminoglycoside very
> quickly (t1/2 ~ 1.5 to 2.5 hours). These individuals have a
> prolonged "drug-free" period of >12 hours which greatly exceeds the
> post antibiotic effect period.
I agree with this. We have been dosing Ag via a ODD method (targeting Cmax
and AUC) at our hospital since 1993 and we haven't got an answer for this
one yet. However you might be interested to know that we are about to
undertake a study in paeds soon, which may shed some light on the matter.
You might argue that while the "drug-free" period may be > 12 hours and
that this may exceed post antibiotic effect this does not exceed the period
of adaptive resistance (but is much closer to exceeding this period than
with adults). Therefore the q24h dose interval may be even more
appropriate for children than adults. It should be noted that we still
don't know how these agents should be dosed most effectively and dosing
q48h in adults may be even better than q24h?
(2) you say ...
> Patients with impaired renal
> function are also sometimes allowed to have prolonged periods with
> low sub MIC concentration.
I don't agree with this. It is our experience that patients with renal
impairment have reduced gentamicin Cl and therefore concentrations tend to
be higher for longer. This may result in vitually the opposite effect and
the concentrations may exceed the MIC for almost the entire dose interval.
Take for example a target AUC of 100 mg/L.h, and the patient has a ClCr of
20 ml/min. Most probably the Cmax will be as low as 9 mg/L, and Cmin will
be approx 1-1.5 mg/L. Many MICs are around this level.
(3) you say...
> Once-a-day treatment is sometimes used in patients where
> the trough concentration is still detectable (>0.5 mg/L). These
> patients are often getting 2-3 times the exposure in terms of AUC
> than they would have received with traditional dosing strategies.
> Increased risk of toxicity may be a problem here.
I agree, this method of dosing does not seem to be logical, but I
understand is still widely advocated.
Regards
Steve
=======================Steve Duffull
Christchurch
New Zealand
Ph +64 3 3815280
Fax +64 3 3640902
Email sduffull.-at-.clear.net.nz
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RE: Aminoglycoside AUC/MIC - William Craig has presented data from
animal studies showing that either Cmax/MIC or AUC/MIC are correlated
strongly with outcome. I will look through the references over the
next several days and forward them to you.
RE: Prolonged "drug free" period - Your study in children will be
quite interesting once completed. Most patients in the US that are
treated with aminoglycosides will also receive a beta-lactam drug in
combination. Without current dosing strategies, it is clear that
aminoglycosides are only modestly effective when administered alone
for non-urinary infections. However, there are very few trials
comparing aminoglycoside monotherapy to other drugs. Beta-lactams
will prevent the adaptive resistance that is seen with
aminoglycosides alone. I agree that we do not really know how long
of a drug free period is optimal. However, I prefer to be cautious
until studies as the one that you describe are completed.
RE: Patients with impaired renal function. If you try to allow
periods of very low aminoglycoside concentrations in patients with
renal dysfunction, concentrations will be typically quite low for a
long period of time. I agree that it is easy to keep concentrations
above the MIC 100% of the time with trough concentration of 0.5-2
mcg/ml which are similar to those achieved with traditional dosing.
However, with the high peak concentration, the total AUC (exposure)
will be much higher. There is always a dilema between providing
greater exposure and allowing the interval to be prolonged
greatly until concentrations are undetectable. The latter is
associated with long periods of low concentrations. Actually, we try
to avoid aminoglycosides in this population altogather.
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Steve Duffull wrote:
> [...] We, in our hospital, have gone towards smaller more
> regular doses eg 500 mg q6h rather than 1000 mg q12h as our standard for
> patients with normal renal function.
We have come to similar conclusions but in case of such short intervals
we usually recommend, when it is possible, a continuous infusion to
reach a steady state level of 15-20 mg/L
> [...] we are about to
> undertake a study in paeds soon, which may shed some light on the matter.
In our hospital we use once-daily tobramycin in pediatric patients with
a dosage adjustment to reach an AUC of 75-100 mg.h/L. We have not
observed toxicity problems with this protocol.
Sincerely
Jean Debord
Laboratoire de Pharmacologie, Faculte de Medecine
2 Rue du Docteur Marcland, 87025 Limoges, France
http://ourworld.compuserve.com/homepages/JDebord
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In published dosing guidelines, it has been typical to target mean
steady-state concentrations of ~15 mg/L. When using an AUC of 100
mg*h/L once daily, the mean steady-state concentration would be
considerably lower (100/24) = 4.2 mg/L. With once daily vancomycin,
I would expect the time below a typical MIC to be quite long.
Perhaps the efficacy should be reviewed rather than the toxicity.
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Dear Randy:
I would agree that for vancomycin an extended interval approach
might not
be the thing, and that a continuous IV approach might be quite useful, on
the other hand. The down side here is only that it ties up a patient's arm.
Otherwise it sounds quite good to me, and we have made some simulations of
this scenario with our Multiple Model dosage design a couple of years ago.
Sincerely,
Roger Jelliffe
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USC Lab of Applied Pharmacokinetics
CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033
Phone (213)342-1300, Fax (213)342-1302
email=jelliffe.aaa.hsc.usc.edu
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